LXRα activation perturbs hepatic insulin signaling and stimulates production of apolipoprotein B-containing lipoproteins

被引:33
作者
Basciano, Heather [1 ]
Miller, Abigale [1 ]
Baker, Chris [1 ]
Naples, Mark [1 ]
Adeli, Khosrow [1 ]
机构
[1] Univ Toronto, Div Clin Biochem, DPLM, Hosp Sick Children,Mol Struct & Funct Res Inst, Toronto, ON M5G 1X8, Canada
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2009年 / 297卷 / 02期
关键词
liver X receptor; very low-density lipoprotein; hamster; LIVER-X-RECEPTOR; LOW-DENSITY LIPOPROTEIN; TRIGLYCERIDE TRANSFER PROTEIN; TYROSINE-PHOSPHATASE; 1B; ELEMENT-BINDING PROTEINS; FATTY-ACID SYNTHESIS; GENE-EXPRESSION; MEDIATED ACTIVATION; LIPID-METABOLISM; SECRETION;
D O I
10.1152/ajpgi.90546.2008
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Basciano H, Miller A, Baker C, Naples M, Adeli K. LXR alpha activation perturbs hepatic insulin signaling and stimulates production of apolipoprotein B-containing lipoproteins. Am J Physiol Gastrointest Liver Physiol 297: G323-G332, 2009. First published June 4, 2009; doi: 10.1152/ajpgi.90546.2008.-Liver X receptor-alpha (LXR alpha) is considered a master regulator of hepatic lipid metabolism; however, little is known about the link between LXR activation, hepatic insulin signaling, and very low-density lipoprotein (VLDL)-apolipoprotein B (apoB) assembly and secretion. Here, we examined the effect of LXR alpha activation on hepatic insulin signaling and apoB-lipoprotein production. In vivo activation of LXR alpha for 7 days using a synthetic LXR agonist, TO901317, in hamsters led to increased plasma triglyceride (TG; 3.6-fold compared with vehicle-treated controls, P = 0.006), apoB (54%, P < 0.0001), and VLDL-TG (eightfold increase compared with vehicle). As expected, LXR stimulation activated maturation of sterol response element binding protein-1c (SREBP-1c) as well as the SREBP-1c target genes steroyl CoA desaturase (SCD) and fatty acid synthase (FAS). Metabolic pulse-chase labeling experiments in primary hamster hepatocytes showed increased stability and secretion of newly synthesized apoB following LXR activation. Microsomal triglyceride transfer protein (MTP) mRNA and protein were unchanged, however, likely because of the relatively short period of treatment and long half-life of MTP mRNA. Examination of hepatic insulin-signaling molecules revealed LXR-mediated reductions in insulin receptor (IR)beta subunit mass (39%, P = 0.014) and insulin receptor substrate (IRS)-1 tyrosine phosphorylation (24%, P = 0.023), as well as increases in protein tyrosine phosphatase (PTP) 1B (29%, P < 0.001) protein mass. In contrast to IRS-1, a twofold increase in IRS-2 mass (228%, P = 0.0037) and a threefold increase in IRS-2 tyrosine phosphorylation (321%, P = 0.012) were observed. In conclusion, LXR activation dysregulates hepatic insulin signaling and leads to a considerable increase in the number of circulating TG-rich VLDL-apoB particles, likely due to enhanced hepatic assembly and secretion of apoB-containing lipoproteins.
引用
收藏
页码:G323 / G332
页数:10
相关论文
共 58 条
[1]   Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity [J].
Araújo, EP ;
De Souza, CT ;
Gasparetti, AL ;
Ueno, M ;
Boschero, AC ;
Saad, MJA ;
Velloso, LA .
ENDOCRINOLOGY, 2005, 146 (03) :1428-1437
[2]   Insulin regulates hepatic apolipoprotein B production independent of the mass or activity of Akt1/PKBα [J].
Au, CS ;
Wagner, A ;
Chong, T ;
Qiu, W ;
Sparks, JD ;
Adeli, K .
METABOLISM-CLINICAL AND EXPERIMENTAL, 2004, 53 (02) :228-235
[3]   Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements [J].
Cagen, LM ;
Deng, X ;
Wilcox, HG ;
Park, EA ;
Raghow, R ;
Elam, MB .
BIOCHEMICAL JOURNAL, 2005, 385 :207-216
[4]   Insulin signaling: Mechanisms altered in insulin resistance [J].
Capeau, J .
M S-MEDECINE SCIENCES, 2003, 19 (8-9) :834-839
[5]   Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster [J].
Carpentier, A ;
Taghibiglou, C ;
Leung, N ;
Szeto, L ;
Van Iderstine, SC ;
Uffelman, KD ;
Buckingham, R ;
Adeli, K ;
Lewis, GF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (32) :28795-28802
[6]   Increased diacylglycerol acyltransferase activity is associated with triglyceride accumulation in tissues of diet-induced insulin-resistant hyperlipidemic hamsters [J].
Casaschi, A ;
Maiyoh, GK ;
Adeli, K ;
Therlault, AG .
METABOLISM-CLINICAL AND EXPERIMENTAL, 2005, 54 (03) :403-409
[7]   Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver [J].
Chen, GX ;
Liang, GS ;
Ou, JF ;
Goldstein, JL ;
Brown, MS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (31) :11245-11250
[8]  
Collins JL, 2004, CURR OPIN DRUG DISC, V7, P692
[9]   LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport [J].
Crestani, M ;
De Fabiani, E ;
Caruso, D ;
Mitro, N ;
Gilardi, F ;
Chacon, ABV ;
Patelli, R ;
Godio, C ;
Galli, G .
BIOCHEMICAL SOCIETY TRANSACTIONS, 2004, 32 :92-96
[10]   Potential regulatory role of the farnesoid X receptor in the metabolic syndrome [J].
Duran-Sandoval, D ;
Cariou, B ;
Fruchart, JC ;
Staels, B .
BIOCHIMIE, 2005, 87 (01) :93-98